Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

• Published in: Molecular psychiatry Vol. 23; no. 5; pp. 1270 - 1277
• Main Authors: Teng, S, Thomson, P A, McCarthy, S, Kramer, M, Muller, S, Lihm, J, Morris, S, Soares, D C, Hennah, W, Harris, S, Camargo, L M, Malkov, V, McIntosh, A M, Millar, J K, Blackwood, D H, Evans, K L, Deary, I J, Porteous, D J, McCombie, W R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2018; Nature Publishing Group
• Subjects: 631/208; 692/699/476; 692/699/476/1333; 692/699/476/1414; 692/699/476/1799; Adult; Aged; Behavioral Sciences; Biological Psychology; Bipolar disorder; Bipolar Disorder - genetics; Brain - metabolism; Case-Control Studies; Cognition; Cognitive ability; Cognitive Dysfunction - genetics; Copy number; Depression; Depressive Disorder, Major - genetics; Disc1 protein; Female; Gene regulation; Genetic aspects; Genetic Predisposition to Disease; Genetic variation; Health aspects; Humans; Interactomes; Male; Medicine; Medicine & Public Health; Mental depression; Mental disorders; Middle Aged; Molecular biology; Nerve Tissue Proteins - genetics; Neurobiology; Neurodevelopmental disorders; Neurosciences; Neurosis; Original; original-article; Pharmacotherapy; Pleiotropy; Polymorphism, Single Nucleotide; Protein Interaction Maps; Psychiatric research; Psychiatry; Psychological aspects; Schizophrenia; Schizophrenia - genetics
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2017.115

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWER across ), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWER across P =0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWER across P =0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.